Adverse reactions : תופעות לוואי

4.8   Undesirable effects
Summary of the safety profile
The safety of rivaroxaban has been evaluated in thirteen pivotal phase III studies (see Table 1).
Overall, 69,608 adult patients in nineteen phase III studies and 488 paediatric patients in two phase II and two phase III studies were exposed to rivaroxaban.
Table 1: Number of patients studied, total daily dose and maximum treatment duration in adult and paediatric phase III studies
Indication                              Number        Total daily dose         Maximum of                                     treatment patients*                              duration
Prevention of venous                    6,097         10 mg                    39 days thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery
Prevention of VTE in medically ill      3,997         10 mg                    39 days patients
Treatment of deep vein thrombosis       6,790         Day 1 - 21: 30 mg        21 months (DVT), pulmonary embolism (PE)                        Day 22 and onwards: and prevention of recurrence                          20 mg
After at least 6 months:
10 mg or 20 mg
Treatment of VTE and prevention of 329                Body weight-adjusted     12 months VTE recurrence in term neonates and                   dose to achieve a children aged less than 18 years                      similar exposure as that following initiation of standard                      observed in adults anticoagulation treatment                             treated for DVT with 20 mg rivaroxaban once daily
Prevention of stroke and systemic       7,750         20 mg                    41 months embolism in patients with non-valvular atrial fibrillation
Prevention of atherothrombotic          10,225        5 mg or 10 mg            31 months events in patients after an acute                     respectively, co- coronary syndrome (ACS)                               administered with either ASA or ASA plus clopidogrel or ticlopidine
Prevention of atherothrombotic          18,244        5 mg co-administered     47 months events in patients with CAD/PAD                       with ASA or 10 mg alone
3,256**       5 mg co-administered     42 months with ASA
*Patients exposed to at least one dose of rivaroxaban
** From the VOYAGER PAD study

The most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (see section 4.4. and ‘Description of selected adverse reactions’ below) (Table 2). The most commonly reported bleedings were epistaxis (4.5%) and gastrointestinal tract haemorrhage (3.8%).
Table 2: Bleeding* and anaemia events rates in patients exposed to rivaroxaban across the completed adult and paediatric phase III studies

Indication                             Any bleeding          Anaemia
Prevention of venous                   6.8% of patients      5.9% of patients thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery
Prevention of VTE in medically ill     12.6% of patients     2.1% of patients patients
Treatment of DVT, PE and               23% of patients       1.6% of patients prevention of recurrence
Treatment of VTE and prevention        39.5% of patients     4.6% of patients of VTE recurrence in term neonates and children aged less than 18 years following initiation of standard anticoagulation treatment
Prevention of stroke and systemic      28 per 100 patient    2.5 per 100 patient embolism in patients with              years                 years non-valvular atrial fibrillation
Prevention of atherothrombotic         22 per 100 patient    1.4 per 100 patient events in patients after an ACS        years                 years
Prevention of atherothrombotic        6.7 per 100          0.15 per 100 events in patients with CAD/PAD       patient years        patient years** 8.38 per 100         0.74 per 100 patient years #      patient years*** #
*      For all rivaroxaban studies all bleeding events are collected, reported and adjudicated.
**       In the COMPASS study, there is a low anaemia incidence as a selective approach to adverse event collection was applied
*** A selective approach to adverse event collection was applied
# From the VOYAGER PAD study

Tabulated list of adverse reactions
The frequencies of adverse reactions reported with Xarelto in adult and paediatric patients are summarised in Table 3 below by system organ class (in MedDRA) and by frequency.

Frequencies are defined as: very common (≥ 1/10) common (≥ 1/100 to < 1/10) uncommon (≥ 1/1,000 to < 1/100) rare (≥ 1/10,000 to < 1/1,000) very rare ( < 1/10,000) not known: (cannot be estimated from the available data)
Table 3: All adverse reactions reported in adult patients in phase III clinical studies or through post-marketing use* and in two phase II and two phase III studies in paediatric patients

Common            Uncommon            Rare                Very rare        Not known 
Blood and lymphatic system disorders
Anaemia (incl.  Thrombocytosis respective      (incl. platelet count laboratory      increased)A,
parameters)     Thrombocytopenia
Immune system disorders
Allergic reaction,                        Anaphylactic dermatitis allergic,                      reactions
Angioedema and                            including allergic oedema                           anaphylactic shock
Nervous system disorders
Dizziness,          Cerebral and headache            intracranial haemorrhage,
syncope
Eye disorders
Eye haemorrhage
(incl. conjunctival haemorrhage)
Cardiac disorders
Tachycardia
Vascular disorders
Hypotension,
haematoma
Respiratory, thoracic and mediastinal disorders
Epistaxis,                                                Eosinophilic haemoptysis                                               pneumonia
Gastrointestinal disorders
Gingival bleeding, Dry mouth gastrointestinal tract haemorrhage
(incl. rectal haemorrhage),
gastrointestinal and abdominal pains, dyspepsia,
nausea,
constipationA,
diarrhoea,
vomitingA
Common            Uncommon               Rare              Very rare         Not known 
Hepatobiliary disorders
Increase in       Hepatic            Jaundice, Bilirubin transaminases     impairment,        conjugated
Increased bilirubin,
increased (with or increased blood    without alkaline           concomitant phosphataseA,      increase of ALT),
increased GGTA     Cholestasis,
Hepatitis (incl.
hepatocellular injury)
Skin and subcutaneous tissue disorders
Pruritus (incl.    Urticaria                               Stevens-Johnson uncommon cases                                             syndrome/ Toxic of generalised                                             Epidermal pruritus), rash,                                           Necrolysis , ecchymosis,                                                DRESS cutaneous and                                              syndrome subcutaneous haemorrhage
Musculoskeletal and connective tissue disorders
Pain in extremityA Haemarthrosis     Muscle                                  Compartment haemorrhage                             syndrome secondary to a bleeding
Renal and urinary disorders
Urogenital tract                                                             Renal haemorrhage                                                                  failure/acute (incl. haematuria                                                            renal failure and                                                                          secondary to a menorrhagiaB),                                                               bleeding renal impairment                                                             sufficient to (incl. blood                                                                 cause creatinine                                                                   hypoperfusion, increased, blood                                                             Anticoagulant- urea increased)-                                                             related nephropathy
General disorders and administration site conditions
Common              Uncommon              Rare                 Very rare          Not known 
FeverA, peripheral Feeling unwell         Localised oedemaA oedema,              (incl. malaise) decreased general strength and energy (incl.
fatigue and asthenia)
Investigations
Increased LDHA,
increased lipaseA,
increased amylaseA
Injury, poisoning and procedural complications
Postprocedural                            Vascular haemorrhage                               pseudoaneurysmC
(incl.
postoperative anaemia, and wound haemorrhage),
contusion,
wound secretionA
A: observed in prevention of VTE in adult patients undergoing elective hip or knee replacement surgery
B: observed in treatment of DVT, PE and prevention of recurrence as very common in women < 55 years
C: observed as uncommon in prevention of atherothrombotic events in patients after an ACS (following percutaneous coronary intervention)
*       A pre-specified selective approach to adverse event collection was applied in selected phase III studies. The incidence of adverse reactions did not increase and no new adverse drug reaction was identified after analysis of these studies.

Description of selected adverse reactions
Due to the pharmacological mode of action, the use of Xarelto may be associated with an increased risk of occult or overt bleeding from any tissue or organ which may result in post haemorrhagic anaemia. The signs, symptoms, and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia (see section 4.9 "Management of bleeding"). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate. The risk of bleedings may be increased in certain patient groups e.g. those patients with uncontrolled severe arterial hypertension and/or on concomitant treatment affecting haemostasis (see section 4.4 "Haemorrhagic risk" ). Menstrual bleeding may be intensified and/or prolonged.
Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea and unexplained shock. In some cases as a consequence of anaemia, symptoms of cardiac ischaemia like chest pain or angina pectoris have been observed.
Known complications secondary to severe bleeding such as compartment syndrome and renal failure due to hypoperfusion, or anticoagulant-related nephropathy have been reported for Xarelto.
Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.

Paediatric population
Treatment of VTE and prevention of VTE recurrence
The safety assessment in children and adolescents is based on the safety data from two phase II and one phase III open-label active controlled studies in paediatric patients aged birth to less than 18 years. The safety findings were generally similar between rivaroxaban and comparator in the various paediatric age groups. Overall, the safety profile in the 412 children and adolescents treated with rivaroxaban was similar to that observed in the adult population and consistent across age subgroups, although assessment is limited by the small number of patients.
In paediatric patients, headache (very common, 16.7%), fever (very common, 11.7%), epistaxis (very common, 11.2%), vomiting (very common, 10.7%), tachycardia (common, 1.5%), increase in bilirubin (common, 1.5%) and bilirubin conjugated increased (uncommon, 0.7%) were reported more frequently as compared to adults. Consistent with adult population, menorrhagia was observed in 6.6% (common) of female adolescents after menarche. Thrombocytopenia as observed in the post-marketing experience in adult population was common (4.6%) in paediatric clinical studies.
The adverse drug reactions in paediatric patients were primarily mild to moderate in severity.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il